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Major Article Sodium Nitroprusside Has Leishmanicidal Activity

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Major Article Sodium Nitroprusside Has Leishmanicidal Activity Revista da Sociedade Brasileira de Medicina Tropical 49(1):68-73, Jan-Feb, 2016 Major Article http://dx.doi.org/10.1590/0037-8682-0266-2015 Sodium nitroprusside has leishmanicidal activity independent of iNOS Natália Yoshie Kawakami[1], Fernanda Tomiotto-Pellissier[1], Allan Henrique Depieri Cataneo[1], Tatiane Marcusso Orsini[1], Ana Paula Fortes Dos Santos Thomazelli[1], Carolina Panis[2], Ivete Conchon-Costa[1] and Wander Rogério Pavanelli[1] [1]. Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brasil. [2]. Laboratório de Mediadores Infl amatórios, Universidade Estadual do Oeste do Paraná, Francisco Beltrão, Paraná, Brasil. ABSTRACT Introduction: Leishmaniasis is a zoonotic disease caused by protozoa of the genus Leishmania. Cutaneous leishmaniasis is the most common form, with millions of new cases worldwide each year. Treatments are ineffective due to the toxicity of existing drugs and the resistance acquired by certain strains of the parasite. Methods: We evaluated the activity of sodium nitroprusside in macrophages infected with Leishmania (Leishmania) amazonensis. Phagocytic and microbicidal activity were evaluated by phagocytosis assay and promastigote recovery, respectively, while cytokine production and nitrite levels were determined by ELISA and by the Griess method. Levels of iNOS and 3-nitrotyrosine were measured by immunocytochemistry. Results: Sodium nitroprusside exhibited in vitro antileishmanial activity at both concentrations tested, reducing the number of amastigotes and recovered promastigotes in macrophages infected with L. amazonensis. At 1.5µg/mL, sodium nitroprusside stimulated levels of TNF-α and nitric oxide, but not IFN-γ. The compound also increased levels of 3-nitrotyrosine, but not expression of iNOS, suggesting that the drug acts as an exogenous source of nitric oxide. Conclusions: Sodium nitroprusside enhances microbicidal activity in Leishmania-infected macrophages by boosting nitric oxide and 3-nitrotyrosine. Keywords: Leishmaniasis. Nitric oxide. 3-nitrotyrosine. Leishmania amazonensis. Sodium nitroprusside. In addition, some strains of the parasite have acquired resistance INTRODUCTION to these drugs(5). Macrophages mount various mechanisms to combat Leishmaniasis, a group of infectious diseases found parasites, including oxidative burst, acidifi cation of vesicles, worldwide, is caused by protozoa of the genus Leishmania. and expression of inducible nitric oxide synthase (iNOS)(6). Approximately 20 to 40 thousand deaths each year are attributed iNOS synthesizes nitric oxide, a highly reactive, membrane- to this disease, which can manifest in various forms with diffusible molecule used to control various pathogens(7). Nitric different symptoms depending on the infecting species and oxide reacts with reactive oxygen species to generate reactive the host immune response. The main forms of the disease are nitrogen species such as peroxynitrite(8), which damage DNA, cutaneous, mucocutaneous, and visceral, of which the cutaneous inhibit enzymes, and peroxidize lipids(9). form is the most common, with 0.7 to 1.2 million new cases Leishmania spp. has evolved several mechanisms to evade each year in 98 countries(1). Pentavalent antimonials are the macrophage activity. For instance, parasites suppress nitric standard treatments, of which meglumine antimoniate and oxide production by taking up L-arginine, a required substrate sodium stibogluconate are the most frequently used(2). However, for iNOS, as well as by inhibiting the release of IFN-γ and these drugs require long treatment regimens and parenteral (3) TNF-α, proinfl ammatory cytokines that stimulate expression or intralesional administration , and cause numerous side (10) effects, including pancreatitis, hepatitis, and cardiotoxicity(3) (4). of this enzyme . These observations suggest that exogenous sources of nitric oxide may potentially be used to control leishmaniasis. Indeed, studies have shown that such sources are active against Leishmania in vitro(11) and in vivo(12), as well as other Corresponding author: Dr. Wander Rogério Pavanelli. (13) e-mail: [email protected] I [email protected] microorganisms, including Strongyloides venezuelensis , (14) (15) Received 25 August 2015 Paracoccidioides brasiliensis , and Trypanosoma cruzi . One Accepted 4 December 2015 such source is sodium nitroprusside (Na2[Fe(CN)5NO]•2H2O), 68 Kawakami NY et al. - Leishmanicidal activity of sodium nitroprusside an inorganic compound(16) active against promastigotes and Nitrite levels axenic amastigotes of Leishmania (Leishmania) amazonensis(17). Nitrite was also determined in the supernatant of cultures In this report, we demonstrate that sodium nitroprusside enhances the microbicidal activity of Leishmania-infected of infected macrophages treated with sodium nitroprusside. macrophages by enhancing production of nitric oxide and Nitric oxide was measured with the Griess reagent according (19) 3-nitrotyrosine. to published methods . Briefl y, aliquots were diluted in 45g/L glycine pH 9.7, and treated for 10 min with cadmium granules previously activated with 5mM CuSO4. Subsequently, 200µL METHODS of this mixture reacted for 10 min at room temperature with an equal volume of Griess reagent. Tubes were then centrifuged Leishmania (Leishmania) amazonensis at 10,845 ×g for 2 min at 25°C, and transferred to 96-well Promastigotes of L. amazonensis (MHOM/BR/1989/166MJO) microplates in triplicate. Absorbance at 550nm was determined were maintained in 199 medium pH 7.18-7.22 (Invitrogen-GIBCO) in a microplate reader. A calibration curve was constructed using supplemented with 10% fetal bovine serum (Invitrogen-GIBCO), dilutions of NaNO2. 10mM HEPES, 0.1% human urine, 0.1% L-glutamine, 10U/mL penicillin, 10µg/mL streptomycin (Invitrogen-GIBCO), and 10% Immunocytochemistry for iNOS and 3-nitrotyrosine sodium bicarbonate. Cultures were grown in 25cm2 fl asks at 24°C. Slides with adherent macrophages were prepared in triplicate as described for the phagocytic assay, and labeled Culture of peritoneal macrophages and by the streptavidin-biotin method (Universal Dako LSAB®+ phagocytosis assay System-HRP Kit, DAKO Japan, Kyoto, Japan) without Macrophages were obtained from the peritoneal cavity microwave pretreatment. Slides were then treated with of BALB/c mice, re-suspended in RPMI 1640 medium pH 10% Triton-X for 15 min, washed with phosphate-buffered 7.2 (Gibco BRL), and incubated for 2h at 37ºC and 5% CO2 saline, and incubated in 1% fetal bovine serum for 30 min. in 24-well plates (5 × 105 cells per well) with 13mm glass Subsequently, slides were probed overnight at 4 ºC with 1:300 coverslips with 200µL RPMI 1640 medium. Adherent cells dilutions of rabbit polyclonal primary antibodies against iNOS were infected for 2h with L. amazonensis promastigotes at a and 3-nitrotyrosine (Santa Cruz Biotechnology), and then ratio of 1:5, washed with phosphate-buffered saline to remove with biotinylated anti-rabbit, anti-mouse, and anti-goat IgG non-phagocytized parasites, and treated for 24h at 37ºC and (LSAB+ System-HRP, DAKO, Japan, Kyoto, Japan) for 2h at 5% CO2 with RPMI 1640 (control) or with 0.5 and 1.5µg/mL room temperature. Negative controls were performed omitting sodium nitroprusside. Subsequently, cells were stained with the primary antibodies. Horseradish peroxidase activity was Giemsa, and 200 cells per sample were imaged at 1,000× under visualized with H2O2 and 3,3'-diaminobenzidine for 5 min, and a CX31RBSFA light microscope (Olympus Optical Co. Ltd., cells were counterstained with Harris hematoxylin (Merck). Tokyo, Japan) to quantify the number of infected macrophages Finally, slides were digitally imaged in color at 400× using a and the average number of amastigotes per macrophage. BX41 photomicroscope (Olympus Optical Co. Ltd., Tokyo, Japan). Representative fi elds of view from 10 images of each replicate Promastigote recovery were scored semi-quantitatively using color deconvolution in ImageJ (NIH, USA). Pixels with intensity 0-255 were Promastigote recovery was performed as previously categorized as strongly positive (3+, intensity 0-60), positive described(18). Briefl y, peritoneal macrophages (5 × 105 cells) (2+, intensity 61-120), weakly positive (1+, intensity were infected with L. amazonensis, treated for 24h at 37ºC and 121-170), and negative (0, intensity 171-230), as previously 5 % CO with 0.5 and 1.5µg/mL sodium nitroprusside, washed 2 described(20). Slides that were not probed with primary antibody with phosphate-buffered saline, and incubated at 24°C with 199 were used as negative control. medium to induce differentiation of intracellular amastigotes into promastigotes. Promastigotes recovered were counted daily in a Neubauer chamber for three days after infection. Statistical analysis Data are reported as mean ± standard error of the mean. Cytokine levels Duplicate datasets from three independent experiments with Supernatants were collected from cultures of infected three animals per experiment were analyzed in Prism GraphPad macrophages 24h after treatment with sodium nitroprusside, 5.00 (GraphPad Software, Inc., USA). Data were found to centrifuged at 460 ×g for 7 min at 4°C, and stored at -80°C be normally distributed by Kolmogorov-Smirnov test, and until analysis. TNF-α, IFN-γ, and IL-12-p70 were determined variances were found to be homogeneous by F test. Treatments by enzyme-linked immunosorbent assay (ELISA) according to were compared by Student’s t-test
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